Landscape of clinically actionable cancer genes: towards precision oncology in Chile

Project Title

Partner Organisations

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

Internal ID

ACT210079

Principal Investigator

ARMISEN YAÑEZ, RICARDO AMADO

Start Date

2021

Publications

Now showing 1 - 10 of 10

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Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis
(2024)
Camilo Tapia-Valladares
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Guillermo Valenzuela
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Evelin González Feliú
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Ignacio Maureira
;
Jessica Toro
<jats:p>Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10−5) and MSK-IMPACT cohorts (p-value = 3.062 × 10−2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.</jats:p>
Scopus© Citations 1 2
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A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer
(2024)
Yanara A. Bernal
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Alejandro Blanco
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Eduardo A. Sagredo
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Karen Oróstica
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ALFARO CORTEZ, IVAN ESTEBAN
Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs. To address this issue, we employed a stringent bioinformatics approach to identify differentially RNA-edited sites (DESs) associated with low or high sensitivity (FDR 0.1, log2 fold change 2.5) according to the IC50 of PARP inhibitors, anthracyclines, and alkylating agents using WGS/RNA-seq data in BC cell lines. We then validated these findings in patients with basal subtype BC. These DESs are mainly located in non-coding regions, but a lesser proportion in coding regions showed predicted deleterious consequences. Notably, some of these DESs are previously reported as oncogenic variants, and in genes related to DNA damage repair, drug metabolism, gene regulation, the cell cycle, and immune response. In patients with BC, we uncovered DESs predominantly in immune response genes, and a subset with a significant association (log-rank test p < 0.05) between RNA editing level in LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 genes, and progression-free survival. Our findings provide a landscape of RNA-edited sites that may be involved in drug response mechanisms, highlighting the value of A>I(G) RNA editing in clinical outcomes for BC.
Scopus© Citations 4 7
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Total mutational load and clinical features as predictors of the metastatic status in lung adenocarcinoma and squamous cell carcinoma patients
(2022)
Karen Y. Oróstica
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Juan Saez-Hidalgo
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Pamela R. de Santiago
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RIVAS VERA, SOLANGE VERÓNICA
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Sebastian Contreras
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Recently, extensive cancer genomic studies have revealed mutational and clinical data of large cohorts of cancer patients. For example, the Pan-Lung Cancer 2016 dataset (part of The Cancer Genome Atlas project), summarises the mutational and clinical profiles of different subtypes of Lung Cancer (LC). Mutational and clinical signatures have been used independently for tumour typification and prediction of metastasis in LC patients. Is it then possible to achieve better typifications and predictions when combining both data streams?</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>In a cohort of 1144 Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LSCC) patients, we studied the number of missense mutations (hereafter, the Total Mutational Load TML) and distribution of clinical variables, for different classes of patients. Using the TML and different sets of clinical variables (tumour stage, age, sex, smoking status, and packs of cigarettes smoked per year), we built Random Forest classification models that calculate the likelihood of developing metastasis.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We found that LC patients different in age, smoking status, and tumour type had significantly different mean TMLs. Although TML was an informative feature, its effect was secondary to the "tumour stage" feature. However, its contribution to the classification is not redundant with the latter; models trained using both TML and tumour stage performed better than models trained using only one of these variables. We found that models trained in the entire dataset (i.e., without using dimensionality reduction techniques) and without resampling achieved the highest performance, with an F1 score of 0.64 (95%CrI [0.62, 0.66]).</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Clinical variables and TML should be considered together when assessing the likelihood of LC patients progressing to metastatic states, as the information these encode is not redundant. Altogether, we provide new evidence of the need for comprehensive diagnostic tools for metastasis.</jats:p> </jats:sec>
2Scopus© Citations 3 1
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MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients
(MDPI AG, 2024-12-22)
RIVAS VERA, SOLANGE VERÓNICA
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Romina V. Sepúlveda
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TAPIA DUFEY, JUAN IGNACIO
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Catalina Estay
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Vicente Soto
<jats:p>Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients. This study utilized a 52-genes next-generation sequencing (NGS) panel to analyze 1560 tumor biopsies from NSCLC patients in Chile, Brazil, and Peru. The RNA sequencing reads and DNA coverage were correlated to improve the detection of the actionable MET exon 14 skipping variant (METex14). The pathogenicity of MET variants of uncertain significance (VUSs) was assessed using bioinformatic methods, based on their predicted driver potential. The effects of the predicted drivers VUS T992I and H1094Y on c-MET signaling activation, proliferation, and migration were evaluated in HEK293T, BEAS-2B, and H1993 cell lines. Subsequently, c-Met inhibitors were tested in 2D and 3D cell cultures, and drug affinity was determined using 3D structure simulations. The prevalence of MET variants in the South American cohort was 8%, and RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis. The novel actionable T992I and H1094Y variants induced proliferation and migration through c-Met/Akt signaling. Both variants showed sensitivity to crizotinib and savolitinib, but the H1094Y variant exhibited reduced sensitivity to capmatinib. These findings highlight the importance of RNA-based METex14 diagnosis and reveal the drug sensitivity profiles of novel actionable MET variants from an understudied patient population.</jats:p>
Scopus© Citations 4 8
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ADAR-Mediated A>I(G) RNA Editing in the Genotoxic Drug Response of Breast Cancer
(2024)
Yanara A. Bernal
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Eduardo Durán
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Isidora Solar
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Eduardo A. Sagredo
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ARMISEN YAÑEZ, RICARDO AMADO
<jats:p>Epitranscriptomics is a field that delves into post-transcriptional changes. Among these modifications, the conversion of adenosine to inosine, traduced as guanosine (A>I(G)), is one of the known RNA-editing mechanisms, catalyzed by ADARs. This type of RNA editing is the most common type of editing in mammals and contributes to biological diversity. Disruption in the A>I(G) RNA-editing balance has been linked to diseases, including several types of cancer. Drug resistance in patients with cancer represents a significant public health concern, contributing to increased mortality rates resulting from therapy non-responsiveness and disease progression, representing the greatest challenge for researchers in this field. The A>I(G) RNA editing is involved in several mechanisms over the immunotherapy and genotoxic drug response and drug resistance. This review investigates the relationship between ADAR1 and specific A>I(G) RNA-edited sites, focusing particularly on breast cancer, and the impact of these sites on DNA damage repair and the immune response over anti-cancer therapy. We address the underlying mechanisms, bioinformatics, and in vitro strategies for the identification and validation of A>I(G) RNA-edited sites. We gathered databases related to A>I(G) RNA editing and cancer and discussed the potential clinical and research implications of understanding A>I(G) RNA-editing patterns. Understanding the intricate role of ADAR1-mediated A>I(G) RNA editing in breast cancer holds significant promise for the development of personalized treatment approaches tailored to individual patients’ A>I(G) RNA-editing profiles.</jats:p>
Scopus© Citations 2 2
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Biobanks and data interoperability in Latin America: engendering high-quality evidence for the global research ecosystem
(Frontiers Media SA, 2024-12-16)
VALDES MEZA, ERICK RICARDO
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LECAROS URZUA, JUAN ALBERTO
<jats:p>Currently, each biobank in Latin America operates with its own set of standards for database creation and management, resulting in a lack of regional and international interoperability. Furthermore, regulations concerning data protection, curation, and the transfer of biological samples and associated data vary significantly from country to country, by complicating efforts to create a unified data-sharing platform. To address these challenges, Latin America should promote the development of an integrated regional network of biobanks to generate high-quality evidence within the global research ecosystem. This initiative will combine regulatory science—focused on interoperability standards across semantic, technical, legal, and organizational dimensions—and meta-science, which assesses the quality of scientific practice. Evidence indicates that harmonized standards in biobanks lead to higher-quality, more reliable data, thereby facilitating the reproducibility of scientific studies. This paper aims to identify and address existing regulatory, policy, and infrastructure gaps in Latin America to establish harmonized interoperability criteria essential for reproducing biomedical studies. Additionally, it seeks to propose minimum standards for regulating biobank networks, which will promote the development of medical products on a global scale, thereby engendering high quality evidence for the global research ecosystem and enhancing Latin America’s integration into it.</jats:p>
Scopus© Citations 2 3
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A snapshot of cancer in Chile II: an update on research, strategies and analytical frameworks for equity, innovation and national development
(Springer Science and Business Media LLC, 2024-12-18)
Cristóbal Vacarezza
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Julieta Araneda
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Pamela Gonzalez
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Oscar Arteaga
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Katherine Marcelain
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Introduction</jats:title> <jats:p>Chile has achieved developed nation status and boasts a life expectancy of 81 + years; however, the healthcare and research systems are unprepared for the social and economic burden of cancer. One decade ago, the authors put forward a comprehensive analysis of cancer infrastructure, together with a series of suggestions on research orientated political policy.</jats:p> </jats:sec><jats:sec> <jats:title>Objectives</jats:title> <jats:p>Provide an update and comment on policy, infrastructure, gender equality, stakeholder participation and new challenges in national oncology. Assess the funding and distribution of cancer investigation. Present actions for the development of oncology research, innovation and patient care.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Triangulating objective system metrics of economic, epidemiological, private and public sector resources together with policy analysis, we assessed cancer burden, infrastructure, and investigation. We analyzed governmental and private-sector cancer databases, complemented by interviews with cancer stakeholders.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Governmental policy and patient advocacy have led to the recognition of cancer burden, a cancer law, and a national cancer plan. Cancer has become the leading cause of death in Chile (59,876 cases and 31,440 cancer deaths in 2022), yet only 0.36% gross domestic product (GDP) is directed to research and development. Inequalities in treatment regimens persist. Prevention policy has lowered tobacco consumption, sugar intake via soft drinks and offered a high coverage of HPV vaccines. A high-quality cancer research community is expanding, and internationally sponsored clinical oncology trials are increasing.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The cancer law has facilitated advancement in policy. Prevention policies have impacted tobacco and sugar intake, while gender equality and care inequality have entered the public forum. Cancer research is stagnated by the lack of investment. Implementation of a cancer registry and biobanking, reinforcement of prevention strategies, development of human resources, promotion of clinical trial infrastructure and investment in new technologies must be placed as a priority to permit advancements in innovation and equitable cancer care.</jats:p> </jats:sec>
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Molecular Analysis of PIK3CA in Metastatic Hormone Receptor-Positive Breast Cancer in Chile: Clinical and Pathological Insights
(2024)
Carla Araya
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Bárbara Mino
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Patricio Le Cerf
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Fancy Gaete
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ARMISEN YAÑEZ, RICARDO AMADO
<jats:p>Breast cancer is the most common cancer among women and a leading cause of cancer-related deaths. PIK3CA gene mutations, which are often present in advanced HR+ breast cancer, can be targeted by alpelisib. However, data on PIK3CA mutations in Chile are limited. Here, we aim to assess the mutational status of PIK3CA in metastatic breast cancer tissues from Chilean patients and describe their clinicopathological characteristics and survival outcomes. We analyzed 102 formalin-fixed, paraffin-embedded metastatic breast cancer samples from 96 patients diagnosed at three Chilean hospitals between 2007 and 2023. PIK3CA mutations were identified using targeted sequencing, and clinicopathological data were collected. We evaluated associations between mutational status, clinicopathological features, and survival. The median age at diagnosis was 56 years. The most common metastatic sites were liver (29.4%), bone (17.6%), and lung/pleura (16.7%). Most patients were HR+ HER2− (83.3%), with 57.3% showing HER2-low status. PIK3CA mutations were present in 40.6% of patients, mainly in exons 7, 9, and 20. No significant associations were found between PIK3CA mutations and clinicopathological characteristics or survival. Our study reveals a high frequency of PIK3CA mutations in HR+ metastatic breast cancer, consistent with global data. The majority of mutations are targetable with alpelisib. The proportion of HER2-low status patients suggests potential benefits from novel HER2-targeted therapies. These findings highlight the need for routine molecular diagnostics in Chile to improve personalized treatment and address economic and access challenges.</jats:p>
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Advances in machine learning for tumour classification in cancer of unknown primary: A mini-review
(2025)
Karen Oróstica
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Felipe Mardones
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Yanara A. Bernal
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Samuel Molina
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Marcos Orchard
Scopus© Citations 3 8
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MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies
(2022)
RIVAS VERA, SOLANGE VERÓNICA
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Arnaldo Marín
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Suraj Samtani
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Evelin González-Feliú
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ARMISEN YAÑEZ, RICARDO AMADO
<jats:p>The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and β-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient’s mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies.</jats:p>
Scopus© Citations 15 16

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